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Clinical Pharmacokinetics May 2011Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa... (Review)
Review
Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. Similar to filgrastim, pegfilgrastim increases the proliferation and differentiation of neutrophils from committed progenitor cells, induces maturation, and enhances the survival and function of mature neutrophils, resulting in dose-dependent increases in neutrophils. After subcutaneous administration, pegfilgrastim exhibits nonlinear pharmacokinetics and exposure to pegfilgrastim increases in more than a dose-proportional manner, suggesting that the clearance of pegfilgrastim decreases with increased dosing. Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells. Pegylation of filgrastim renders renal clearance insignificant, which was demonstrated in bilaterally nephrectomized rats and confirmed in subjects with renal impairment. As a result, the neutrophil-mediated clearance is the predominant elimination pathway for pegfilgrastim. During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until onset of neutrophil recovery. Pegfilgrastim concentrations are sustained longer in patients with profound neutropenia. Evidence supports the use of a postnadir absolute neutrophil count (ANC) of ≥ 1 × 109/L as a surrogate marker threshold for the clearance of pegfilgrastim to subtherapeutic levels. After repeated administration of pegfilgrastim, the peak concentrations of pegfilgrastim decrease, likely due to increased neutrophil and neutrophil precursor mass. A pharmacokinetic-pharmacodynamic model was developed to describe the pharmacokinetic and ANC profiles of pegfilgrastim; the analysis supported that 100 μg/kg was an adequate weight-based dose of pegfilgrastim and predicted that 6 mg would be an optimal fixed dose of pegfilgrastim to simplify treatment. Data from a pivotal study confirmed that a once-per-chemotherapy-cycle injection of pegfilgrastim at 6 mg was as safe and effective as 11 daily injections of filgrastim at 5 μg/kg in reducing neutropenia and its complications in patients with breast cancer receiving four cycles of doxorubicin/docetaxel chemotherapy. Because of the highly efficient regulation of pegfilgrastim clearance via neutrophils and neutrophil precursors, a single fixed dose of pegfilgrastim can be given once per chemotherapy cycle in conjunction with a variety of myelosuppressive chemotherapy regimens.
Topics: Animals; Antineoplastic Agents; Drug Dosage Calculations; Drug Interactions; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Models, Biological; Neutropenia; Neutrophils; Polyethylene Glycols; Recombinant Proteins
PubMed: 21456630
DOI: 10.2165/11586040-000000000-00000 -
Drugs 2002Pegfilgrastim is a covalent conjugant of filgrastim (a recombinant human granulocyte colony-stimulating factor) and monomethoxypolyethylene glycol. It is administered as... (Review)
Review
Pegfilgrastim is a covalent conjugant of filgrastim (a recombinant human granulocyte colony-stimulating factor) and monomethoxypolyethylene glycol. It is administered as a single dose per myelosuppressive chemotherapy cycle to decrease the incidence of infection, as manifest by febrile neutropenia, in patients with nonmyeloid cancer. Pegfilgrastim increases the terminal elimination half-life and decreases the apparent serum clearance of the drug in patients with nonmyeloid cancer. Serum concentrations of pegfilgrastim remain elevated during neutropenia but decline when the neutrophil count increases. In phase III trials in patients with breast cancer and in a phase II trial in patients with non-Hodgkin's lymphoma or Hodgkin's disease, the mean duration of grade 4 neutropenia and the time to absolute neutrophil recovery during cycle 1 of chemotherapy was similar in recipients of single-dose pegfilgrastim or daily filgrastim. In the larger of two phase III trials in patients with breast cancer, the incidence of febrile neutropenia over four cycles of chemotherapy was significantly lower in recipients of single-dose pegfilgrastim than that in recipients of daily injections of filgrastim. Moreover, the mean duration of grade 4 neutropenia in cycles 2 to 4 of chemotherapy was significantly lower in recipients of pegfilgrastim than that in recipients of daily filgrastim. In comparative trials, there were no differences in the incidence and severity of adverse events, including skeletal pain, between single-dose pegfilgrastim and daily filgrastim in patients with nonmyeloid cancer receiving myelosuppressive chemotherapy.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Filgrastim; Granulocyte Colony-Stimulating Factor; Half-Life; Hodgkin Disease; Humans; Immunocompromised Host; Lymphoma, Non-Hodgkin; Neoplasms; Neutropenia; Pain; Polyethylene Glycols; Recombinant Proteins
PubMed: 12010086
DOI: 10.2165/00003495-200262080-00012 -
BioDrugs : Clinical Immunotherapeutics,... Feb 2019Pegfilgrastim-jmdb/MYL-1401H (FULPHILA™) [hereafter referred to as pegfilgrastim-jmdb] is a biosimilar of the reference pegylated recombinant granulocyte... (Review)
Review
Pegfilgrastim-jmdb/MYL-1401H (FULPHILA™) [hereafter referred to as pegfilgrastim-jmdb] is a biosimilar of the reference pegylated recombinant granulocyte colony-stimulating factor pegfilgrastim. It is approved for use in patients receiving chemotherapy for malignancy to decrease the incidence of infection, as manifested by febrile neutropenia, in the USA and to reduce the duration of neutropenia and the incidence of febrile neutropenia in the EU. Pegfilgrastim-jmdb has similar physicochemical characteristics and functional properties to those of US- and EU-sourced reference pegfilgrastim, and the pharmacodynamic and pharmacokinetic similarity of the agents has also been demonstrated in healthy volunteers. Pegfilgrastim-jmdb demonstrated clinical efficacy equivalent to that of EU-sourced reference pegfilgrastim in patients with newly diagnosed Stage II/III breast cancer receiving neoadjuvant or adjuvant chemotherapy and was generally well tolerated in this patient population. The overall safety profile and immunogenic potential of the two agents was similar. The role of reference pegfilgrastim in the management of chemotherapy-induced neutropenia is well established and pegfilgrastim-jmdb provides an effective biosimilar alternative for patients requiring pegfilgrastim therapy.
Topics: Biosimilar Pharmaceuticals; Breast Neoplasms; Female; Filgrastim; Humans; Neutropenia; Polyethylene Glycols; Randomized Controlled Trials as Topic
PubMed: 30701419
DOI: 10.1007/s40259-019-00334-9 -
BioDrugs : Clinical Immunotherapeutics,... Apr 2019LA-EP2006 (Ziextenzo) is the fifth biosimilar of pegfilgrastim, a pegylated recombinant granulocyte colony-stimulating factor, to be approved in the EU. It is approved... (Review)
Review
LA-EP2006 (Ziextenzo) is the fifth biosimilar of pegfilgrastim, a pegylated recombinant granulocyte colony-stimulating factor, to be approved in the EU. It is approved for use in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) to reduce the duration of neutropenia and the incidence of febrile neutropenia. LA-EP2006 matched reference pegfilgrastim in terms of physicochemical characteristics and functional properties, and the pharmacodynamic and pharmacokinetic similarity of the medicines has been shown in healthy volunteers. LA-EP2006 demonstrated clinical efficacy equivalent to that of EU-sourced reference pegfilgrastim in adult women with breast cancer receiving chemotherapy. The tolerability and safety profile of and the incidence of anti-drug antibodies with LA-EP2006 were similar to those of EU-sourced reference pegfilgrastim in this patient population. The role of reference pegfilgrastim in the management of chemotherapy-induced neutropenia is well established and LA-EP2006 provides an effective biosimilar alternative for patients requiring pegfilgrastim therapy.
Topics: Adult; Biosimilar Pharmaceuticals; Breast Neoplasms; Double-Blind Method; Female; Filgrastim; Humans; Neutropenia; Polyethylene Glycols; Randomized Controlled Trials as Topic; Therapeutic Equivalency
PubMed: 30887256
DOI: 10.1007/s40259-019-00348-3 -
Expert Opinion on Biological Therapy Dec 2002Granulocyte colony stimulating factor (G-CSF) has proven efficacy in the prophylaxis of chemotherapy induced neutropenia and is associated with a reduction in the... (Review)
Review
Granulocyte colony stimulating factor (G-CSF) has proven efficacy in the prophylaxis of chemotherapy induced neutropenia and is associated with a reduction in the duration of neutropenia, febrile neutropenia, hospitalisation and intravenous antibiotic use. It is an effective mobiliser of peripheral blood progenitor cells and is used in many countries to mobilise and provide a source of stem cells for autologous and allogeneic bone marrow transplantation. The longevity of G-CSF action is limited by its short half-life, necessitating daily injections. Pegfilgrastim (Neulasta, Amgen, Inc.) is a novel form of filgrastim (G-CSF) with a sustained duration of action. Single dose pegfilgrastim has been shown to be as safe and effective as daily filgrastim in reducing the incidence of chemotherapy induced neutropenia. Pegfilgrastim provides clinical and quality of life benefits for patients as a result of its once per cycle administration. It is licenced in the US for use in the prophylaxis and treatment of chemotherapy induced neutropenia. Clinical trials to evaluate its ability to mobilise peripheral blood progenitor cells are ongoing.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia; Polyethylene Glycols; Recombinant Proteins
PubMed: 12517276
DOI: 10.1517/14712598.2.8.985 -
Current Medical Research and Opinion May 2023Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that may occur in patients with malignancies receiving myelosuppressive chemotherapy. FN requires... (Review)
Review
Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that may occur in patients with malignancies receiving myelosuppressive chemotherapy. FN requires early therapeutic intervention since it is associated with increased hospitalizations and high mortality risk of 5%-20%. FN-related hospitalizations are higher in patients with myeloid malignancies than in those with solid tumors due to the myelotoxicity of chemotherapy regimens and the compromised bone marrow function. FN increases the burden of cancer by causing chemotherapy dose reductions and delays. The administration of the first granulocyte colony-stimulating factor (G-CSF) filgrastim reduced the incidence and duration of FN in patients undergoing chemotherapy. Filgrastim later evolved into pegfilgrastim, which has a longer half-life than filgrastim and is associated with a lower rate of severe neutropenia, chemotherapy dose reduction, and treatment delay. Nine million patients have received pegfilgrastim since its approval in early 2002. The pegfilgrastim on-body injector (OBI) is an innovative device facilitating the time-released auto-injection of pegfilgrastim approximately 27 h after chemotherapy, as clinically recommended for the prevention of FN, thus eliminating the need for a next-day hospital visit. Since its introduction in 2015, one million patients with cancer have received pegfilgrastim using the OBI. Subsequently, the device was approved in the United States (US), European Union, Latin America, and Japan, with studies and a postmarketing commitment demonstrating device reliability. A recent prospective observational study conducted in the US demonstrated that the OBI substantially improved the adherence to and compliance with clinically recommended pegfilgrastim therapy; patients receiving pegfilgrastim the OBI experienced a lower incidence of FN than those receiving alternatives for FN prophylaxis. This review discusses the evolution of G-CSFs leading to the development of the OBI, current recommendations for G-CSF prophylaxis in the clinic, continued evidence supporting next-day pegfilgrastim administration, and improvements in patient care made possible with the OBI.
Topics: Humans; United States; Filgrastim; Reproducibility of Results; Granulocyte Colony-Stimulating Factor; Polyethylene Glycols; Neoplasms; Chemotherapy-Induced Febrile Neutropenia; Recombinant Proteins; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36976784
DOI: 10.1080/03007995.2023.2196197 -
Pharmacotherapy Aug 2003Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) with a long half-life and sustained duration of action. Pegfilgrastim is created with pegylation... (Review)
Review
Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) with a long half-life and sustained duration of action. Pegfilgrastim is created with pegylation technology, whereby a 20-kD polyethylene glycol moiety is conjugated to filgrastim (recombinant human G-CSF), resulting in a larger molecule. Consequently, its renal clearance by glomerular filtration is minimized, making neutrophil-mediated clearance the predominant route of elimination. Preclinical animal data have shown that the clearance of pegfilgrastim depends on dosage and absolute neutrophil count, with pegfilgrastim having a longer circulating half-life and more sustained duration of action than filgrastim. The biologic effect of pegfilgrastim is prolonged in a neutropenic setting because few mature neutrophils are available to mediate its elimination. Clinical trials have suggested that neutrophil-mediated clearance of pegfilgrastim may be self-regulating and may therefore be specific to each patient's hematopoietic recovery.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Clinical Trials as Topic; Drug Evaluation, Preclinical; Filgrastim; Granulocyte Colony-Stimulating Factor; Half-Life; Humans; Metabolic Clearance Rate; Neutropenia; Polyethylene Glycols; Recombinant Proteins
PubMed: 12921217
DOI: 10.1592/phco.23.9.9s.32888 -
Pegfilgrastim-Induced Bone Pain: A Review on Incidence, Risk Factors, and Evidence-Based Management.The Annals of Pharmacotherapy Sep 2017To review the incidence, risk factors, and management of pegfilgrastim-induced bone pain (PIBP). (Review)
Review
OBJECTIVE
To review the incidence, risk factors, and management of pegfilgrastim-induced bone pain (PIBP).
DATA SOURCES
PubMed was searched from 1980 to March 31, 2017, using the terms pegfilgrastim and bone pain.
STUDY SELECTION AND DATA EXTRACTION
English-language, human studies and reviews assessing the incidence, risk factors, and management of PIBP were incorporated.
DATA SYNTHESIS
A total of 3 randomized, prospective studies and 2 retrospective studies evaluated pharmacological management of PIBP. Naproxen compared with placebo demonstrated a reduction in the degree, incidence, and duration of bone pain secondary to pegfilgrastim. Loratadine was not effective in reducing the incidence of bone pain prophylactically, but a retrospective study evaluating dual antihistamine blockade with loratadine and famotidine demonstrated a decreased incidence in bone pain when administered before pegfilgrastim.
CONCLUSION
Naproxen is effective at managing PIBP. Although commonly used, antihistamines have a paucity of data supporting their use. Dose reductions of pegfilgrastim and opioids may also be potential management options; however, data supporting these treatment modalities are scarce.
Topics: Analgesics, Opioid; Bone Diseases; Evidence-Based Medicine; Filgrastim; Histamine Antagonists; Humans; Incidence; Naproxen; Nociceptive Pain; Pain Management; Polyethylene Glycols; Risk Factors
PubMed: 28423916
DOI: 10.1177/1060028017706373 -
Radiology Dec 2022
Topics: Humans; Aortitis; Filgrastim; Polyethylene Glycols; Tomography, X-Ray Computed; Drug Prescriptions
PubMed: 35943341
DOI: 10.1148/radiol.221712 -
Blood Cancer Journal May 2017The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule... (Comparative Study)
Comparative Study Randomized Controlled Trial
The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P<0.0001, each), and further reduced by 2 days (P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P<0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Filgrastim; Humans; Length of Stay; Leukemia, Myeloid, Acute; Male; Middle Aged; Platelet Transfusion; Polyethylene Glycols; Survival Rate
PubMed: 28548643
DOI: 10.1038/bcj.2017.45